title: Transcriptional repression of Bmp2 by p21(Waf1/Cip1) links quiescence to neural stem cell maintenance.
abstract: Relative quiescence and self renewal are defining features of adult stem cells, but their potential coordination remains unclear. Subependymal neural stem cells (NSCs) lacking cyclin-dependent kinase (CDK) inhibitor (CKI) 1a (p21) exhibit rapid expansion that is followed by their permanent loss later in life. Here we demonstrate that transcription of the gene encoding bone morphogenetic protein 2 (Bmp2) in NSCs is under the direct negative control of p21 through actions that are independent of CDK. Loss of p21 in NSCs results in increased levels of secreted BMP2, which induce premature terminal differentiation of multipotent NSCs into mature non-neurogenic astrocytes in an autocrine and/or paracrine manner. We also show that the cell-nonautonomous p21-null phenotype is modulated by the Noggin-rich environment of the subependymal niche. The dual function that we describe here provides a physiological example of combined cell-autonomous and cell-nonautonomous functions of p21 with implications in self renewal, linking the relative quiescence of adult stem cells to their longevity and potentiality.
authors.affiliation: 1] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [2] Departamento de Biología Celular, Universidad de Valencia, Valencia, Spain. [3].
authors.forename: Eva
authors.initials: E
authors.lastname: Porlan
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Morante-Redolat
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Marqués-Torrejón
authors.forename: Celia
authors.initials: C
authors.lastname: Andreu-Agulló
authors.forename: Carmen
authors.initials: C
authors.lastname: Carneiro
authors.forename: Esther
authors.initials: E
authors.lastname: Gómez-Ibarlucea
authors.forename: Atenea
authors.initials: A
authors.lastname: Soto
authors.forename: Anxo
authors.initials: A
authors.lastname: Vidal
authors.forename: Sacri R
authors.initials: SR
authors.lastname: Ferrón
authors.forename: Isabel
authors.initials: I
authors.lastname: Fariñas
mesh_terms: D000367:Age Factors; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D001973:Bromodeoxyuridine; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002461:Cell Line, Transformed; D017077:Culture Media, Conditioned / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D014411:Neoplastic Stem Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D001973:Bromodeoxyuridine; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D000099176:Noggin Protein; C525719:Bmp2 protein, mouse; C493957:Cdkn1a protein, mouse